Project Summary/Abstract The recessive ?curly whiskers? (cw) mutations in mice impact hair morphology, and one allele (cwthd) has been previously shown to also generate a single-gene, dominantly-inherited barrier to graft transplantation. However, a modern, molecular-genetic assessment of these variants has been lacking because: 1) the cwthd allele is no longer extant, and 2) no causative gene has yet been assigned to this fascinating and pleiotropic locus. To overcome these obstacles, we have made two recent advances. First, we have used a positional approach to provisionally assign an mRNA splicing defect in the hephaestin-like 1 gene (Hephl1) to the original, spontaneous cw allele. Second, we have established a segregating, congenic strain that will allow direct evaluation of cw as a minor histocompatibility (H) locus. From this platform we now propose short-term experiments designed: 1) to confirm our assignment of the cw mutation to the Hephl1 gene, and 2) to test, initially by skin- graft exchange assay, whether cw (like the cwthd mutation) can generate a barrier to graft compatibility. These experiments, while primarily focusing on the cw allele we currently possess, will also include an independent, spontaneous allele of cw we are in the process of importing (cw2J), and at least one engineered Hephl1 variant. The research we propose here also promises to enhance research activity at CCSU (by providing undergraduate and master?s-level students with a variety of defined, entry-level projects), and to set-the-stage for a longer-term developmental and immunogenetic characterization of the set of curly whiskers variants we propose to assemble?and the orthologous human disorder(s) they may model.